TGFβ (Transforming Growth Factor-β) Blockade Induces a Human-Like Disease in a Nondissecting Mouse Model of Abdominal Aortic Aneurysm

Lareyre, Fabien; Clément, Marc; Raffort, Juliette; Pohlod, Stefanie; Patel, Mitesh; Esposito, Bruno; Master, Leanne; Finigan, Alison; Vandestienne, Marie; Stergiopulos, Nikolaos; Taleb, Soraya; Trachet, Bram; Mallat, Ziad

doi:10.1161/atvbaha.117.309999

Cited by 74 publications

(88 citation statements)

References 30 publications

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“…During the progression of AAA, accumulation, and activation of inflammatory cells takes place in the aorta. These inflammatory cells play a key and substantial role in vascular remodeling 9,29 . In our study, we found a significant amount of CD 68 (M1 type macrophage) and activated macrophage Mac-2 in PPE treated aorta.…”

Section: Discussionmentioning

confidence: 99%

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Nanoparticle-based targeted delivery of pentagalloyl glucose reverses elastase-induced abdominal aortic aneurysm and restores aorta to the healthy state in mice

Dhital

Vyavahare

2019

Preprint

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Abbreviations AAA -Abdominal aortic aneurysm BSA -Bovine serum albumin DIR -1,1-Dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide EL-GNP -elastin antibody conjugated gold nanoparticle EL-NP -Elastin antibody-conjugated blank nanoparticles EL-PGG-NP -Elastin antibody-conjugated and PGG-loaded albumin NPs FACS -Fluorescence-activated cell sorting MMP-Matrix metalloproteinase NPs -Nanoparticles PGG-Pentagalloyl glucose TGF--Tumor Growth Factor beta IL-Interleukine ABSTRACT Aim: Abdominal aortic aneurysms (AAA) is a life-threatening weakening and expansion of the abdominal aorta due to inflammatory cell infiltration and gradual degeneration of extracellular matrix (ECM). There are no pharmacological therapies to treat AAA. We tested the hypothesis that nanoparticle (NP) therapy that targets degraded elastin and delivers anti-inflammatory, anti-oxidative, and ECM stabilizing agent, pentagalloyl glucose (PGG) will reverse advance stage aneurysm in an elastase-induced mouse model of AAA. Method and Results:Porcine pancreatic elastase (PPE) was applied periadventitially to the infrarenal aorta in mice and AAA was allowed to develop for 14 days. Nanoparticles loaded with PGG (EL-PGG-NPs) were then delivered via IV route at 14-day and 21-day (10 mg/kg of body weight). A control group of mice received no therapy. The targeting of NPs to the AAA site was confirmed with fluorescent dye marked NPs and gold NPs.Animals were sacrificed at 28-d. We found that targeted PGG therapy reversed the AAA by decreasing matrix metalloproteinases MMP-9 and MMP-2, and the infiltration of macrophages in the medial layer. The increase in diameter of the aorta was reversed to healthy controls. Moreover, PGG treatment restored degraded elastic lamina and increased the circumferential strain of aneurysmal aorta to the healthy levels. Conclusion:Our results support that site-specific delivery of PGG with targeted nanoparticles can be used to treat already developed AAA. Such therapy can reverse inflammatory markers and restore arterial homeostasis.

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Section: Discussionmentioning

confidence: 99%

“…TGFβ1 plays a key role in the progression of aneurysm. Others have shown that TGFβ1 administration exacerbates aneurysms 20,9 . IHC staining for TGFβ1 was performed to assess the presence of TGFβ1 in the aneurysmal aorta, in PPE and PGG treated aorta sections.…”

Section: Pgg Treatment Decreases Tgfβ1 In the Aneurysmal Aortamentioning

confidence: 99%

Nanoparticle-based targeted delivery of pentagalloyl glucose reverses elastase-induced abdominal aortic aneurysm and restores aorta to the healthy state in mice

Dhital

Vyavahare

2019

Preprint

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“…30 Details on the development and characterisation of these mouse models have been previously published. 29,30 Procedures. For all experiments, we used male, C57Bl/6J, 8-week-old mice (Charles River, UK).…”

Section: Experimental Mouse Modelsmentioning

confidence: 99%

Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates

Paige

Clément

Lareyre

et al. 2018

Preprint

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Objective: The Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture. Approach: Using data from 2,863 participants with AAA from nine prospective cohorts, ageand sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death. Results: After adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [-0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05). Conclusions:Our proof-of-principle data are compatible with the concept that IL-6 transsignalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.

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“…Arrows = free ends of ruptured media. C ) Schematic of the new murine AAA model reported by Lareyre et al 14 Elastase is applied topically to the abdominal aorta, and mice are injected with anti-TGF-β antibodies. Aortas undergo medial degeneration with breaks in elastic laminae (arrows) as well as dilation that includes all 3 layers (intima, media, adventitia).…”

Section: Figurementioning

confidence: 99%

“…14 They suggest that none of the existing animal AAA models “reproduces and combines the major features of human AAA,” which they list as: extracellular matrix proteolysis, degeneration and loss of vascular smooth muscle cells, alteration of endothelial cells, intraluminal thrombosis, infiltration of innate and adaptive immune cells, progressive aortic dilation in the absence of medial dissection, and aortic wall rupture. Lareyre et al criticize current animal AAA models as either: 1) models of intramural hemorrhage/dissection without true aneurysmal dilation [e.g., the angiotensin II-infusion model (Figure) as well as models relying on lysyl oxidase inhibition or mineralocorticoid agonists combined with high salt); or 2) models of aortic dilation that fail to progress to rupture (e.g., the elastase or calcium chloride models).…”

mentioning

confidence: 99%